Microtubule-associated protein 1B rescues memory decline in Alzheimer’s disease model miceName : Dr. Fuyuki Mitsuyama
Affliation : Professor
University : Fujita Health University
Country : Japan
Background: The classic pathologies seen in Alzheimer’s disease (AD) are amyloid plaques1 and neurofibrillary tangles2, but synapse and spine loss3-5 have been recognised as new pathologies. Microtubules are thought to be less plentiful in spines6, so it has been thought that spine shape change and molecular transportation in spines is performed mainly by actin. However, following reports of the intraspinal invasion of microtubules using microtubule-preservative fixation methods or live observation7-13, alternative mechanisms require investigation. Microtubule-associated protein 1B (MAP1B) has microtubule conserving and polymerising effects and is overexpressed in Fragile X syndrome, in which spines are thin and elongated14. It is speculated that the polymerisation of these intraspinal microtubules by MAP1B may restore spine integrity and rescue AD symptoms, however, this has not yet been proven.
Methods: We injected a Map1b-lentivirus chimera to the hemi-hippocampus (right side) of nine Tg6799 mice15 at 101 days old. The spatial working memory of injected mice was assessed by spontaneous alternation in the Y-maze (n = 9) and compared with non-injected Tg6799 mice (n = 10). We also investigated the change in spines resulting from MAP1B overexpression in cultured neurons of wild type mice from the same strain as the model mice (C57/BL6). To investigate the relationship between microtubules and enlarged spines, cells co-transfected with GFP and a Map1b-lentivirus chimera were simultaneously stained with anti-tubulin antibody. We also investigated whether administration of the Map1b-lentivirus chimera to the hemi-hippocampus of AD model mice causes recovery of the postsynaptic density.
Results: Here we show that a Map1b-lentivirus chimera injected to the hemi-hippocampus of AD model mice rescues memory impairment. Spatial working memory assessed by the Y-maze in injected mice improved to almost normal levels within 2 days of the injection. A Map1b-lentivirus chimera also produced microtubule-dense enlarged spines in the cultured neurons of normal C57BL mice. Map1b-lentivirus chimera injection also restored reduced postsynaptic densities in AD model mice, as assessed by protein immunoblots.
Conclusions: These results suggest that MAP1B-dependent intraspinal microtubules may enhance the structural integrity of spines, restoring spine shrinkage, improving the bidirectional transportation of memory-facilitating molecules, and rescuing memory impairment in AD model mice.